tbuckley/cabot-search huggingface dataset:
IMMU-39. EFFICACY OF IMMUNE CHECKPOINT INHIBITORS IN GLIOBLASTOMA FROM REAL-WORLD DATA ANALYSIS
Authors: Timothy Stuhlmiller, Jameson Quinn, Alaa Awawda, Nicolas Blondin, Fabio Iwamoto, Burt Nabors, Charles Redfern, Asher Wasserman, Zachariah Cole, Mark Shapiro, Santosh Kesari
Journal: Neuro-Oncology (2023)

Abstract Immune checkpoint inhibitors (ICIs) failed to show efficacy in a randomized trial in glioblastoma (GBM). We utilized the patient-led XCELSIOR platform (NCT03793088) to evaluate ICIs in real-world GBM treatment. XCELSIOR centralizes EMR data from all care sites, creating longitudinal, source-verified data. Identity verification permits accurate overall survival (OS) calculations. As of 6/8/2023, 726 GBM patients were enrolled in XCELSIOR. Median diagnosis date was 1/13/2021 and median age was 56. Seventy-five patients (10%) received ICIs: 53 received pembrolizumab (71%) and 26 received nivolumab (35%) including 12 with ipilimumab (16%). Median days from diagnosis to ICI initiation was 263 days with 22 patients treated at 1st line, 39 at 2nd line, and 14 at 3rd line or later. Data was annotated for 71 patients treated with ICIs and 394 patients not treated with ICIs (no-ICI). Median OS (mOS) from diagnosis for all ICI patients vs. no-ICI was 4.95 years (95% CI 2.18-NR) vs. 1.75 years (1.56-2.03, p &amp;lt; 0.0001). Key features in the ICI cohort were 46% methylated MGMT, 47% gross total resection, 61% exposed to non-SOC agents besides ICI. Creating a propensity score matched cohort for these features, ICI vs. no-ICI had a numerically increased but non-significant mOS of 2.58 years (1.78-NR, n=62) vs. 2.05 years (1.76-2.61, n=113) but a 5-year survival rate of 44% for ICI vs. 16% for no-ICI. Optune use was similar, 39% ICI and 29% no-ICI. Common non-SOC agents used in the ICI cohort were everolimus (11%), osimertinib (8%), lenvatinib (7%), abemaciclib (7%), and neoantigen peptide vaccines (7%). Among unmethylated MGMT patients, mOS was 1.78 years for ICI vs. 1.8 years for no-ICI. These data suggest activity of ICIs for a subset of GBM patients, but do not support use in patients with unmethylated MGMT. Next steps will focus on discrete combination regimens in this evolving data.
NCOG-09. EXAMINING THE CLINICAL UTILITY OF NEXT GENERATION SEQUENCING IN ADULT GLIOBLASTOMA – A SINGLE CENTER RETROSPECTIVE STUDY
Authors: Jerica Lomax, Thomas Taylor, Xiao-Tang Kong, Daniela Bota
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Over the last 2 decades, the use of molecular targeted therapy has revolutionized the cancer treatment landscape and transformed the outcomes and disease prognoses of several cancer entities. The success of targeted therapy is closely tied to the advent of commercially available next generation sequencing (NGS) which has expanded our understanding and knowledge of the genetic drivers and mutations present in a variety of tumors. Unfortunately, in glioblastoma (GBM), the overall effectiveness of targeted therapies remains limited.1 Nonetheless, NGS for GBM patients has been integrated into the standard practice of many neuro-oncologists and is encouraged by the National Comprehensive Cancer Network (NCCN) Guidelines. The purpose of this retrospective chart review is to evaluate how NGS is incorporated into the management of glioblastoma at a single center academic institution. METHODS We identified 85 patients with pathologically confirmed GBM who had NGS done from January 2014-March 2021. The clinical records of all patients were reviewed to denote the frequency of clinical trial enrollment or off-label use of targeted therapy based on the results of NGS. We also denoted the time point in the disease course when NGS was ordered and the trend of frequency of ordering NGS from January 2014-December 2020. RESULTS 28.2% (95% CI 19 to 39.1%) of patients received treatment based on the results of NGS. 8% were enrolled in a clinical trial and 20% were treated with off-label use of targeted therapy at the time of disease progression. There was no statistically significant survival difference seen between patients who had treatment done based on results of NGS compared to those who did not. CONCLUSION NGS results are used to guide treatment or clinical trial enrollment in a significant number of glioblastoma patients, however, the clinical efficacy of this treatment is yet to be determined.
IMMU-35. G-AMINOBUTYRIC ACID DRIVES GLIOBLASTOMA IN FEMALES BY ACTIVATING THE COMPLEMENT SYSTEM
Authors: Defne Bayik, Asmita Pathak, Diana Chin, Feng Lin, Antonio Iavarone, Justin Lathia
Journal: Neuro-Oncology (2023)

Abstract Interaction between tumor and neural cells drives the progression of glioblastoma (GBM), which is characterized by enhanced immunosuppressive myeloid cell accumulation. Our previous results revealed that myeloid-derived suppressor cell subsets (MDSCs) play a central role in tumorigenesis in a sex-specific manner, with monocytic MDSCs (mMDSCs) accumulating in male tumors and granulocytic MDSCs (gMDSCs) correlating with a worse outcome in females. However, host factors governing sex differences in MDSC subset activity remained unknown. Here, we report that g-aminobutyric acid (GABA) receptor expression by gMDSCs informs their sex-specific behavior. We observed that only female gMDSCs but not male gMDSCs or mMDSCs from either sex respond to GABA by upregulating the antiviral innate immune pathway. As part of this signature, GABA-stimulated female gMDSCs had higher complement 1qa (C1qa) expression. To test the potential role of the GABA pathway on GBM outcome, we tested the GABA analogue pregabalin in preclinical models. Female mice treated with pregabalin succumbed to disease earlier, consistent with our previous observation that gMDSCs have a central role in GBM progression in females. In contrast, pregabalin treatment had no effect in male mice with tumors or immunocompromised female mice. To further evaluate whether C1q is a relevant physiological target, we performed single-cell sequencing of tumor-infiltrating versus circulating MDSC subsets and detected high levels of C1q expression in gMDSCs from tumors. C1q KO transgenic female mice had significantly better outcomes compared to wild-type littermates upon implantation with syngeneic mouse GBM lines, while C1q expression status did not impact the outcome in males. Correspondingly, only in female patients C1q expression correlated with poor prognosis. Collectively, these results identify a neuron-immune-cancer communication axis and indicate that GABA and C1q alter anti-tumor immune responses in a sex-specific manner. These results support the future assessment of the GABA pathway and complement inhibitors as potential immunotherapy agents.
CTNI-75. EFFICACY AND SAFETY OF LAROTRECTINIB IN PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS: AN UPDATED ANALYSIS
Authors: Sébastien Perreault, François Doz, Birgit Geoerger, Antoine Italiano, Ulrik Lassen, Anna Nilsson, Karsten Nysom, Jean-Philippine Spano, Ricarda Norenberg, Vadim Bernard-Gauthier, Esther de la Cuesta, Alexander Drilon, Theodore Laetsch, Cornelis van Tilburg
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Larotrectinib is a highly selective TRK inhibitor approved for tumor-agnostic use in patients with various tumor types, including primary CNS tumors. Here, we report the independent central review and updated data on patients with TRK fusion-positive primary CNS tumors. METHODS Patients with TRK fusion primary CNS tumors enrolled in two clinical trials (NCT02637687, NCT02576431) were included. Responses were independent review committee (IRC)-assessed. RESULTS As of July 2022, 41 patients were eligible for response assessment by IRC. The median age at enrollment was 11 years (range 1-79). Tumor histologic groups included: high-grade glioma (HGG; n=25), low-grade glioma (LGG; n=9), and other (n=7). Sixteen (39%) patients had received ≥ 2 prior systemic therapies. For all patients, objective response rate (ORR) was 22% (95% CI 11–38): one complete response, eight partial response, 20 stable disease, and 12 progressive disease. For pediatric patients (n=28), the ORR was 29% (95% CI 13–49). For pediatric patients with HGG and LGG, ORRs were 14% (95% CI 2–43) and 57% (95% CI 18–90), respectively. The disease control rates at 24 weeks were 54% (95% CI 37–69) and 71% (95% CI 51–87) for all patients and pediatric patients, respectively. Medians for time to response, duration of response, progression-free survival, and overall survival (OS) were 1.9 months, 12.2 months (95% CI 3.7–not estimable), 11.1 months (95% CI 3.6–19.8), and not reached, respectively. The 48-month OS rate was 52%. Treatment duration ranged from 1 to 50+ months. Treatment-related adverse events (TRAEs) were mostly Grade 1/2. No patients discontinued treatment due to TRAEs. CONCLUSION Larotrectinib demonstrated rapid, durable responses and a manageable safety profile in patients with TRK fusion primary CNS tumors. This supports the wider adoption of next-generation sequencing panels that include NTRK gene fusions when testing patients with CNS tumors.
EPID-25. SIX CONSECUTIVE CASES OF PRIMARY INTRACRANIAL SARCOMA IN CHILDREN IN TWO PRIVATE INSTITUTIONS FROM LIMA DURING COVID-19 PANDEMIC
Authors: Rolando Lovaton-Espadin, Wesley Alaba-Garcia
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Peruvian health system was severely impacted by COVID-19 pandemic. Public hospitals were saturated by patients with COVID-19 rapidly. Many patients had to seek medical attention for other health conditions in private institutions. This situation was also observed in pediatric patients with brain tumors. The objective of the present study was to describe clinical and neuroimaging characteristics from pediatric patients diagnosed with brain tumors in two private institutions fron Lima-Peru during COVID-19 pandemic. METHODS Descriptive study of cases of brain tumor in patients aged less than 18 years observed in two private institutions from Lima-Peru from March 2020 to December 2021. RESULTS Six consecutive cases of intracranial tumors were detected during a large part of COVID-19 pandemic's first year (October 2020 to March 2021), all of them with diagnosis of primary intracranial sarcoma . Before the pandemic, the last primary intracranial sarcoma in children operated occurred in June 2018, and was the only case that year. CONCLUSION The present study found an unusual frequency of primary intracranial sarcoma in children in two private institutions from Lima-Peru during COVID-19 pandemic.
IMMU-23. FRUCTOSE METABOLISM IN MICROGLIA PROMOTES GLIOBLASTOMA GROWTH
Authors: Leah Billingham, Si Wang, Kaylee Zilinger, TzuYi Chia, Joshua Katz, Gustavo Ignacio Vazquez Cervantes, Hanxiou Wan, Lauren Boland, David Hou, Catalina Lee-Chang, Jason Miska
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most common brain malignancy in adults and has a dismal prognosis. Advances in standard-of-care treatments for GBM have not kept pace with those for other malignancies, in part due to the inefficacy of immunotherapies in treating GBM. The tumor microenvironment (TME) of GBM is heavily populated with pro-tumorigenic tumor-associated macrophages (TAMs) and lacks robust infiltration of T cells. Given that the number of TAMs in the TME correlates with poor prognosis, understanding the mechanisms by which they thrive is essential for discovering new therapies. Bulk RNASeq data from mouse tumors indicates that the fructose transporter, SLC2A5, is highly expressed on TAMs relative to peripheral myeloid cells. Furthermore, human glioblastoma single cell RNASeq (scRNASeq) data indicates that SLC2A5 is expressed specifically on microglia, the tissue resident macrophage of the brain. To assess the necessity of SLC2A5 in microglia, we orthotopically implanted CT2A or QPP4 glioblastoma cells into wild-type mice and mice lacking SLC2A5 (SLC2A5 KO mice). We observed a significant increase in median survival in SLC2A5 KO mice compared to wild-type mice. This indicates a necessity of fructose metabolism in microglia to promote tumorigenesis. Upon ex vivo analysis of the immune compartment of the TME, we observed that microglial cells from tumors in SLC2A5 KO mice have higher expression of MHC-II and PDL1 molecules on the cell surface compared to those from wild-type mice. Additionally, the CD4:CD8 T cell ratio in tumors from SLC2A5 KO mice was lower than that in tumors from wild-type mice. These data suggest that fructose metabolism in microglia facilitates an immunosuppressive phenotype that promotes GBM progression.
IMMU-41. IMMUNOLOGICAL TARGETING OF SLOW-CYCLING CELLS TO PREVENT RECURRENCE IN GBM
Authors: Avirup Chakraborty, Cole Conforti, Olusegun Sobanjo, Ethan Hodge, Mia Engelbart, Paul Castillo, Catherine Flores, Jianping Huang, Duane Mitchell, Loic Deleyrolle
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most common primary malignancy of the central nervous system (CNS) and is typically fatal due to recurrence despite aggressive treatment. Targeting residual cells after surgical tumor removal is challenging due to the infiltrative nature of GBM. It is crucial to develop effective adjuvant therapies that can combat the drivers of disease recurrence. Traditional anticancer treatments tend to eliminate rapidly dividing cells while sparing dormant or infrequently dividing populations. Numerous studies have identified slow-cycling cells (SCCs) in various cancers, including high-grade glioma, which are resistant to therapies. Our laboratory has discovered SCCs in high-grade glioma, which are highly infiltrative and treatment-resistant cells responsible for driving recurrence. It is imperative to develop an effective strategy to specifically eliminate this cell population in order to reduce recurrence and improve survival rates. Importantly, these cells have a defined cellular niche that contains potentially immunogenic neoantigens, making them suitable targets for immune-based therapies. Our primary objective is to utilize SCC antigens in the form of RNA or peptides to stimulate the immune system and enable it to identify and target treatment-resistant clones. By focusing on these crucial drivers of recurrence, our aim is to achieve strong and effective tumor control. Our research findings indicate that our approach effectively primes T cells to identify and target treatment-resistant cells in glioma. Our results demonstrated that T cells specific to slow-cycling cells (SCC-T cells) showed greater activation when exposed to treatment-resistant tumor cells, as evidenced by increased differentiation of CD8 cells and enhanced development of effector and memory cells. Furthermore, SCC-T cells exhibited the highest level of anti-tumor activity, resulting in a significant reduction in tumor cell proliferation and an increase in apoptosis. Taken together, these results highlight the effectiveness and superiority of our SCC-based immunotherapy platform in targeting treatment-resistant glioblastoma cells.
EXTH-54. GB13 IS A POTENT TREATMENT FOR IL13RA2-EXPRESSING GBM AND DMG AND IMPROVES STANDARD-OF-CARE THERAPY
Authors: Julian Rechberger, Liang Zhang, Harrison Laukhuff, Maija Woodruff, Jann Sarkaria, David Daniels, Randy Schrecengost
Journal: Neuro-Oncology (2023)

Abstract GB13 is a novel biologic therapy in the final stages of preclinical development for the treatment of glioblastoma (GBM) and H3 K27-altered diffuse midline glioma (DMG) that has received Orphan Drug Designation by the Food and Drug Administration for treatment of malignant gliomas. GB13 targets a specific tumor-restricted receptor of interleukin 13 called interleukin 13 receptor alpha 2 (IL13Rα2). IL13Rα2 is highly expressed in malignant gliomas and, importantly, is not expressed on non-cancerous cells of the brain. GB13 consists of an engineered proprietary mutant of IL13, which binds exclusively to IL13Rα2, and is fused to a highly cytotoxic exotoxin molecule. In vitro data demonstrate that GB13 potently kills IL13Rα2+ cancer cells while sparing non-cancerous cells. These characteristics make GB13 an attractive agent for safe and efficacious targeting of tumor cells expressing IL13Rα2 in upcoming clinical trials. In the current studies, we employed patient-derived GBM and DMG cell and animal models to provide key conclusions that support GB13 as an effective treatment option for gliomas in the clinic. First, we demonstrated that single acute infusions of GB13 by enhanced delivery (CED) is effective at decreasing orthotopic tumor volumes and increasing animal survival and that a long-term infusion can more significantly extend animal survival. Second, we determined that IL13Rα2 is requisite for GB13 activity as tumors that do not express the receptor are insensitive to the cytotoxic effects of GB13, demonstrating a precise and clear biomarker for clinical trial patient selection. Finally, we determined that GB13 works in concert with clinical standard-of-care radiation therapy to increase cell death, compared to radiation alone. Based on this work, we and our clinical collaborators are confident that the current work confirms GB13 has many important characteristics as an exciting therapy, which continues development towards a Phase I clinical trial for both GBM and pediatric DMG.
CTIM-04. TOPICAL DIPHENCYPRONE IMMUNOTHERAPY FOR CUTANEOUS NEUROFIBROMAS ASSOCIATED WITH NF1, A PHASE 1 STUDY
Authors: Rebecca Brown, Nicholas Gulati, Dina Poplauski, Jade Young
Journal: Neuro-Oncology (2023)

Abstract Neurofibromatosis type 1 (NF1) is a tumor predisposition syndrome affecting ~1 in 2500 people. Affected patients develop peripheral nerve sheath tumors of the skin known as cutaneous neurofibromas (CN), with variable disease burden ranging from 0-1 tumors to over 10,000. Patients cite deformity, pain, and pruritus from CN as one of the most difficult features of the disease. To date, there are no practical or effective pharmacotherapies for these tumors. This is a single-center, phase I, open label trial to evaluate the safety, tolerability, and efficacy of diphencyprone (DPCP), a topical hapten compound that induces a delayed-type. Twelve adult patients with NF1 and &amp;gt;3 CN of maximum diameter &amp;gt;4 mm were enrolled. DPCP 0.04% ointment was administered topically once weekly to up to 20 cNFs in a localized body region for 10 weeks. Endpoints included (primary) safety and tolerability of DPCP ointment via CTCAE reporting and subjective scoring of symptoms. Efficacy was assessed using RECIST (Response Evaluation Criteria in Solid Tumors) guidelines in conjunction with whole body photography and manual tri-axial tumor measurements. One treated tumor is tracked throughout the study with optical coherence tomography (OCT) imaging. Skin biopsies of a CN and surrounding tissue are collected at baseline, on Day 17 after treatment initiation, and four weeks post-treatment for exploratory endpoints qRT-PCR, single-cell RNA sequencing, and immunohistochemistry to detect differences in immune cell infiltration, tumor cell density, and transcriptional changes throughout the treatment course. Clinical trial information: NCT05438290.
INNV-15. OPTIMIZING THE ROLE OF THE ADVANCED PRACTICE PROVIDER IN THE MANAGEMENT OF A SINGLE PATIENT INVESTIGATIONAL NEW DRUG (IND)
Authors: Susanne D Jacobs, Margaret O Johnson, Elizabeth S Miller, Mallika Patel, Mary L Affronti
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Single patient Investigational New Drug (IND) applications are a way through which experimental therapies may be accessed by patients with cancer especially if a clinical trial is not available. However, initiating and managing a single patient IND is complex. We will outline our approach used at an academic teaching center to leverage the skills and scope of practice of advanced practice providers (APPs) to facilitate successful initiation and monitoring of individual patients who may be receiving an investigational drug under a single patient IND. METHODS We describe a single case of a 52-year-old male with a left thalamic glioblastoma treated with standard of care and monitored off therapy from May 2021 until November 2022. Extended genomic profiling of his tumor at time of biopsy revealed a FGFR3-TACC3 fusion and MGMT promoter methylation, and the decision was made to pursue a single patient IND for anlotinib for use in combination with temozolomide. RESULTS Following permission from the US Food and Drug Administration (FDA) to proceed and IRB chair concurrence, the MD and APP conferred with the investigational and clinical pharmacists regarding procurement and dispensing of the drug, in addition to surveillance and associated toxicities. The APP obtained consent, collected data on monitoring parameters and adverse events, checked for drug interactions with the patient’s routine medications, ordered and reviewed all treatment related MRIs, labs, and EKGs, and coordinated with ophthalmology for baseline and monthly eye exams. Performance of initial and follow-up exams, ongoing toxicity review and management, and care coordination with the local oncology team were completed by the APP. CONCLUSION As first point of contact for the patient and family, the APP plays a key role in glioma research within the multidisciplinary team by providing ongoing symptom management, education, and monitoring for patients receiving investigational drugs.
MODL-44. DEVELOPMENT OF A NOVEL, PERSONALIZED DRUG SENSITIVITY SCORE TO ASSESS TUMOR KILLING AND TOXICITY WITHIN AN ORGANOTYPIC BRAIN SLICE CULTURE PLATFORM
Authors: Breanna Mann, Xiaopei Zhang, Noah Bell, Adebimpe Adefolaju, Morrent Thang, Rajaneekar Dasari, Krishna Kanchi, Alain Valdivia, Yang Yang, Andrew Buckley, Vivien Lettry, Carolyn Quinsey, Yasmeen Rauf, David Kram, Noah Cassidy, Cyrus Vaziri, David L Corcoran, Stephen Rego, Yuchao Jiang, Lee M Graves, Denise Dunn, Scott Floyd, Albert Baldwin, Shawn Hingtgen, Andrew B Satterlee
Journal: Neuro-Oncology (2023)

Abstract Development of new therapeutics for clinical use requires balancing tumor killing and off-target toxicity to normal tissue. We have established an organotypic brain slice culture (OBSC) platform which enables us to assess both on- and off-target drug effects via engraftment, treatment, and analysis of cell lines and uncultured patient brain tumor tissue. We have used OBSCs to test seven cell lines, ten patient tissues, and normal brain tissue against a panel of eleven different therapeutics. To determine a normalized comparison among drugs of differing potencies, we have established a drug sensitivity score (DSS) which combines both direct tumor killing via bioluminescence imaging and off-target toxicity via propidium iodide staining. Our ability to define these values independently allows us to generate normalized therapeutic window ratios for each drug-tumor-OBSC interaction. From these results, 11 different parameters, including those commonly used to define drug activity such as IC10, IC50, and area under the curve, were assessed and combined into a single ranked score which combines more than 100 data points. This algorithm enables relative comparisons among tumor responses to several drugs with less bias toward more potent compounds which produce correspondingly high off-target toxicity. Trends across DSSs for every tumor indicate that we can calculate scores throughout the entire scoring range. While we find that patient tumor tissue is generally more sensitive to treatment than cell lines, there is still a wide distribution of patient tumor sensitivities among tumor types and therapeutics. Additionally, our DSS can detect differences in tumor sensitivity after a single gene alteration in RAD18. In summary, our DSS algorithm and scoring system provides a summarized, normalized way to assess both on-target killing and off-target toxicity, allowing more comprehensive comparisons of drugs with varying potency.